Changes in Gut Microbiome May Be Connected to Alzheimer Disease and Mild Cognitive Impairment

As research into the connection between the gut microbiome and the brain continues, Psychiatric Times discussed a new study on Alzheimer disease (AD), mild cognitive impairment (MCI), and gut microbiota with researchers. Lead authors Leigh A. Frame, PhD, MS, and Alison Warren, DAOM, MSHS, shared insights on their recent work “The microbiota–gut–brain axis in mild cognitive impairment and Alzheimer's disease: a scoping review of human studies,” which found a connection between gut bacteria composition and cognitive differences of MCI and AD.

Psychiatric Times: Can you provide a brief overview of the data and results from your recent paper?

Leigh A. Frame, PhD, MS; and Alison Warren, DAOM, MSHS: This scoping review synthesized findings from 58 human studies, including cross-sectional analyses, case-control studies, small clinical trials, and meta-analyses, examining the gut microbiome in mild cognitive impairment and Alzheimer disease. Across studies, individuals with MCI and AD consistently showed altered gut microbiota composition compared with cognitively healthy older adults, reflective of dysbiosis (microbiomes characterized by an imbalance of gut microbes).

For example, multiple studies reported enrichment of taxa within the Pseudomonadota (formerly Proteobacteria) and Actinomycetota phyla in Alzheimer’s disease, alongside reductions in taxa often associated with gut barrier integrity and metabolic homeostasis. While specific compositional changes were consistent, overall microbial diversity showed more variable patterns, with significant diversity reductions observed more consistently in AD than in MCI. Beyond composition, several studies using predictive functional profiling and metabolomic approaches suggested reduced microbial activity in energy metabolism and immune-related pathways in AD. Taken together, these findings point toward gut dysbiosis as a potential contributor to systemic inflammation and altered immune signaling relevant to the pathogenesis and symptom presentation in cognitive decline.

PT:Did you find a difference in gut bacteria between mild cognitive impairment and Alzheimer disease?

Drs Frame and Warren: Yes, differences emerged both in degree and pattern of gut bacteria present in persons between these distinct disease stages. Alzheimer’s disease was associated with more consistent and pronounced dysbiosis, including repeated findings of increased Escherichia coli and other inflammatory-associated taxa across independent cohorts. In contrast, MCI studies showed more variability, with some reporting enrichment of taxa such as Faecalibacterium or Roseburia, organisms often linked to short-chain fatty acid production, while others showed early signs of dysbiosis similar to AD.

This heterogeneity in MCI may reflect a transitional stage, where microbiome changes are emerging but not yet fully consolidated. The distinction suggests that microbiome alterations may evolve along the continuum from healthy aging to MCI and ultimately Alzheimer’s disease, similar to, and in tandem with, the continuum of symptom progression we see in MCI to Alzheimer’s disease. We know that the pathogenesis of several neurological diseases begins decades earlier and often involves gastrointestinal symptoms, starting in the early stages and continuing through the disease progression. This pattern of dysbiosis may reflect early signs and symptoms of this transition state in this regard, that may serve as early indicators of brain health decline.

PT: Was there a particular element of your review findings you found surprising or most important?

Drs Frame and Warren: One of the most important findings was not the identification of a single defining microbe, but rather the confirmation that Alzheimer’s disease and mild cognitive impairment are associated with broader patterns of microbial imbalance and functional disruption. We did not anticipate finding a single causative organism, as the gut microbiome is a complex, interactive ecosystem influenced by several lifestyle and genetic factors, including diet, medications, immune status, stress, and aging.

Instead, the review highlighted that changes in microbial communities and their metabolic activity—such as alterations in energy metabolism and immune-related pathways—appear to be more informative than any individual taxon. While Escherichia coli was one of the few species reported consistently across Alzheimer’s disease studies, this likely reflects a shift toward a more inflammatory microbial environment rather than the presence of a single disease-causing microbe. This ecosystem-level perspective is critical for understanding how the microbiome may contribute to neuroinflammation and cognitive decline.

The emerging evidence of functional changes, such as reduced microbial pathways related to energy production and immune modulation, further supported this. Collectively, this suggests that what gut bacteria are doing may matter as much as (or more than) which bacteria are present, offering a more nuanced understanding of how the microbiome could influence neuroinflammation.

PT: What should practicing clinicians keep in mind when thinking about the use of probiotic or dietary interventions?

Drs Frame and Warren: While there is promise, clinicians should approach microbiome-targeted interventions with measured caution. These strategies are best understood as adjunctive, supportive approaches rather than disease-modifying treatments. Several small randomized trials included in the review reported modest improvements in cognitive test scores following probiotic supplementation, including formulations containing specific Bifidobacterium strains such as B. longum. However, these trials were typically short in duration, involved small sample sizes (and, thus, limited diversity of microbiomes), and varied widely in strains and outcomes measured.

For example, some trials demonstrated improvements in select cognitive domains or slower rates of memory loss, while others showed no significant global cognitive change. As such, probiotics should not be positioned as treatments for MCI or Alzheimer’s disease, but may be considered low-risk, supportive interventions in carefully selected patients.

Dietary studies, including those examining Mediterranean-style diets, modified ketogenic diets, and the MIND diet (Mediterranean–DASH Intervention for Neurodegenerative Delay), have demonstrated shifts in gut microbial composition and metabolite profiles that are relevant to brain health, though they do not establish causality. For example, one study examined a modified Mediterranean-ketogenic diet in 11 patients with Alzheimer’s disease compared to 6 controls, finding shifts in both bacterial and fungal gut populations, though the small sample size limits generalizability. These dietary patterns are consistently associated with higher intake of plant-based fibers, polyphenols, and unsaturated fats, which support microbial diversity and the production of metabolites such as short-chain fatty acids that are involved in immune regulation and gut barrier integrity.

Evidence from human and mechanistic studies suggests that these dietary patterns may influence neuroinflammation indirectly by modulating the microbiota–gut–brain–immune axis, including effects on systemic inflammation, oxidative stress, and microglial activation. However, it is important to emphasize that no specific diet or probiotic intervention should be viewed as a stand-alone treatment for mild cognitive impairment or Alzheimer’s disease. Rather, dietary patterns that support gut health and metabolic resilience can be discussed as part of broader lifestyle guidance that aligns with existing recommendations for cardiometabolic, inflammatory, and overall brain health.

That being said, we know that diet is a powerful lifestyle factor that plays a crucial role in disease prevention and perhaps the slowing of disease progression. Food first, is typically our motto, and supplement when needed—emphasis on “supplement” rather than “replace.” We know our brains and bodies require nutrients to function properly, and that brain health is intimately tied to gut health. This is such an exciting field of study because we know we have limited control over genes, but the pathway between gut health and brain health (including neurocognitive and neuropsychiatric disorders) is opportunistically modifiable. Therefore, an overall healthy diet that also includes prebiotic and probiotic foods can go a long way in maintaining and promoting brain health.

PT: What role do you think gut microbiota might play in helping evaluate MCI/dementias in the future?

Drs Frame and Warren: Gut microbiota are unlikely to function as a standalone diagnostic tool for MCI or Alzheimer’s disease, but they may play an important role in earlier risk identification and stratification within a broader, multi-domain evaluation framework. Our review and related work suggest that microbiome alterations reflect changes in immune function, metabolic signaling, and gut barrier integrity—processes that often precede overt cognitive symptoms and are increasingly recognized as relevant to neurodegeneration.

Patterns of microbial composition, reduced diversity, and shifts in microbial metabolic pathways—particularly those related to inflammation, energy metabolism, and immune modulation—may help identify individuals at elevated risk before clinical impairment becomes apparent. As discussed in our 2024 work, the microbiome may serve as an integrative readout of cumulative lifestyle, dietary, and environmental exposures, offering insight into neuroimmune vulnerability over time.

In the future, microbiome data could complement established biomarkers, such as neuroimaging, fluid biomarkers, genetic risk factors, and clinical assessments, to support earlier identification of at-risk individuals and more personalized prevention strategies. Longitudinal human studies are still needed to determine predictive value and clinical utility, but this approach holds promise for shifting dementia research and care toward earlier intervention.

Finally, even in the absence of “perfect” microbiota analysis that is readily available to all patients, integrating questions about gastrointestinal health in clinical encounters can confer important information in a clinical assessment. We are seeing important conversations around this in the domains of neuronutrition and nutritional psychiatry, for example. Clinicians can therefore integrate their knowledge of a patient’s gastrointestinal and brain health to help guide them toward well-being.

PT: What do you hope the next steps of research are on the relationship of Alzheimer disease/MCI and microbiota?

Drs Frame and Warren: Future research should focus on longitudinal human studies with standardized microbiome and cognitive assessment methods, exploring the pathogenesis process. Greater use of strain-level sequencing, metabolomics, and functional assays will help clarify mechanisms linking gut dysbiosis to neuroinflammation and neuronal injury. Importantly, larger and longer intervention trials are needed to determine whether modifying the microbiome can meaningfully influence cognitive outcomes or disease trajectories. These studies are essential for responsibly translating microbiome research into clinical practice. Most importantly, translational research that promotes this clinical knowledge into practice, and equips clinicians with tools and resources will be crucial.

Dr Frame is executive director of the GW Office of Integrative Medicine & Health and associate professor of Clinical Research and Leadership and Physician Assistant Studies at the George Washington University School of Medicine & Health Sciences. A translational health leader and microbiome researcher, her work focuses on the microbiota–gut–brain–immune axis, fatty acids, postbiotic metabolites, and nutritional immunology. She cohosts the GW Integrative Medicine Podcast and cofounded the GW Resiliency & Wellbeing Center.

Dr Warren is an adjunct assistant professor at the George Washington University School of Medicine & Health Sciences and an instructor at Harvard University Extension School. Her transdisciplinary research focuses on the microbiota–gut–brain axis, neuroinflammation, psychology, and cognitive aging, with an emphasis on translating emerging science into clinically relevant prevention and care strategies. Her work integrates neuroscience, integrative and lifestyle medicine, and translational science to support real-world application in primary care and aging populations.